Linked Life Data

17545622

Source:http://linkedlifedata.com/resource/pubmed/id/17545622

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2007-6-4
pubmed:abstractText
Proton pumps like the vacuolar-type H+ ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose- and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5408-17
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:17545622-Animals, pubmed-meshheading:17545622-Antineoplastic Agents, Phytogenic, pubmed-meshheading:17545622-Apoptosis, pubmed-meshheading:17545622-Caspases, pubmed-meshheading:17545622-Cell Growth Processes, pubmed-meshheading:17545622-Cell Line, Tumor, pubmed-meshheading:17545622-Cytosol, pubmed-meshheading:17545622-Drug Synergism, pubmed-meshheading:17545622-Enzyme Inhibitors, pubmed-meshheading:17545622-Female, pubmed-meshheading:17545622-Humans, pubmed-meshheading:17545622-Hydrogen-Ion Concentration, pubmed-meshheading:17545622-Jurkat Cells, pubmed-meshheading:17545622-Lymphoma, B-Cell, pubmed-meshheading:17545622-Mice, pubmed-meshheading:17545622-Mice, SCID, pubmed-meshheading:17545622-Omeprazole, pubmed-meshheading:17545622-Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, pubmed-meshheading:17545622-Proton Pumps, pubmed-meshheading:17545622-Reactive Oxygen Species, pubmed-meshheading:17545622-Vinblastine, pubmed-meshheading:17545622-Xenograft Model Antitumor Assays
pubmed:year
2007
pubmed:articleTitle
Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species.
pubmed:affiliation
Department of Drug Research and Evaluation, Pharmacogenetic, Drug Resistance, and Experimental Therapeutic Section, Istituto Superiore di Sanità, Rome, Italy. Angelo.demilito@iss.it
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't